Malondialdehyde modification of myelin oligodendrocyte glycoprotein leads to increased immunogenicity and
Maja Wållberg1, Jonas Bergquist, Adnane Achour
1Department of Clinical Neurosciences, Applied Immunology, Centre for Molecular Medicine, Karolinska University Hospital at Solna, Stockholm, Sweden.
Abstract:
Self proteins may become autoantigenic through structural modification. We studied malondialdehydation of recombinant rat (rr) myelin oligodendrocyte glycoprotein (MOG), an autoantigen in multiple sclerosis. Malondialdehyde (MDA) modification changed protein weight and charge, the location of these adducts being mapped by Fourier transform ion cyclotron resonance. Molecular modelling revealed significant differences in the MDA-rrMOG three-dimensional structure. DBA/1 mice immunised with MDA-rrMOG developed greater proliferative responses and more severe experimental autoimmune encephalomyelitis than mice immunised with unmodified rrMOG. MDA-rrMOG was taken up more effectively by antigen-presenting cells (APC), at least partially through scavenger receptors. Exposure to MDA-rrMOG led to increased expression of IL-23, IL-12 and IL-12R, indicating a role not only for increased antigen uptake but also for activation of APC. We thus provide biochemical, structural, immunological and clinical data that suggest that the post-translationally modified form of this myelin autoantigen is a more relevant form of the molecule.
Insights
Structural modification of myelin oligodendrocyte glycoprotein (MOG) by malondialdehyde (MDA) enhances its autoantigenicity. This modified MOG triggers more severe experimental autoimmune encephalomyelitis in mice, suggesting its relevance in multiple sclerosis pathogenesis.
Area of Science:
- Neuroimmunology
- Protein Chemistry
- Structural Biology
Background:
- Self-proteins can become autoantigenic following structural modifications.
- Myelin oligodendrocyte glycoprotein (MOG) is a key autoantigen implicated in multiple sclerosis (MS).
Purpose of the Study:
- To investigate the impact of malondialdehyde (MDA) modification on recombinant rat MOG (rrMOG).
- To assess the structural, immunological, and clinical consequences of MDA-rrMOG in an experimental autoimmune encephalomyelitis (EAE) model.
Main Methods:
- Fourier transform ion cyclotron resonance mass spectrometry to map MDA adducts.
- Molecular modeling to analyze structural changes in MDA-rrMOG.
- Immunization of DBA/1 mice with MDA-rrMOG and unmodified rrMOG to assess immune responses and EAE severity.
- Analysis of antigen-presenting cell (APC) uptake and cytokine expression (IL-23, IL-12, IL-12R).
Main Results:
- MDA modification altered rrMOG's weight, charge, and three-dimensional structure.
- Mice immunized with MDA-rrMOG exhibited heightened proliferative responses and more severe EAE.
- MDA-rrMOG showed increased uptake by APCs, partly via scavenger receptors.
- Exposure to MDA-rrMOG upregulated IL-23, IL-12, and IL-12R expression in APCs.
Conclusions:
- Post-translationally modified MOG, specifically MDA-rrMOG, is a more potent autoantigen.
- MDA modification enhances MOG's ability to induce autoimmune responses and EAE.
- These findings highlight the significance of protein modification in the pathogenesis of autoimmune diseases like MS.
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